Anti-VEGF agents pass into the bloodstream after intravitreal injection, and can affect systemic VEGF levels. Although safe in the general population, safety in at-risk populations remains unclear. A large meta-analysis of patients treated with ranibizumab (RBZ) for AMD, RVO and DME pointed to imbalances in the incidence of cerebrovascular accident (CVA), death, and wound healing complications in DME patients, but not AMD or RVO (Avery, et al. ARVO 2013). Two meta-analyses have pointed to an increased risk of CVA from 0.5 mg RBZ over 0.3 mg or sham in AMD. We hypothesized that there could be a potential safety signal in diabetics receiving prolonged high monthly doses of anti-VEGF agents.

An increased incidence of mortality and CVA was observed in diabetics treated with monthly AFL or 0.5 mg RBZ for 2 years. A similar, but not statistically significant trend was seen in ATEs. These results must be interpreted with caution as they are derived from 4 small trials. In addition, the lack of patient-level data impairs interpretation and prevents time to death comparisons, but the imbalance in death developed in the second year of treatment. Further detailed review of the cause deaths will help with interpretation of these findings.